Targeted therapies represent the future of oncology treatment. Toward this end, we have recently identified and subsequently validated novel drug targets in four independent settings that are effective and specific to tumors bearing mutations in common oncogenes and tumor suppressor genes. Our functional genetic approach, based on the genetic principle of synthetic lethality, utilizes a state-of-the-art high-throughput RNA interference and small molecule screening platform, genetically defined cell systems as well as patient-derived cultures for target discovery, advanced computational biology methods using publically available datasets to prioritize targets, and patient-derived xenografts to validate thee novel targets. Through the development and expansion of this integrative discovery engine, we will generate a gold standard synthetic lethal database for several major oncogenes/tumor suppressor genes and identify novel drug targets for three major cancer types. In the very near future this pipeline could be utilized for iterative clinical trial design and personalized cancer treatment.